A Chemistry for Incorporation of Selenium into DNA‐Encoded Libraries

Abstract

Conventional direct C−H selenylation suffers from simple selenation with limited atom economy and complicated reaction system. In this work, we designed benzoselenazolone as a novel bifunctional selenide reagent for both off‐ and on‐DNA C−H selenylation under rhodium(III) catalysis. We show that using benzoselenazolone allowed production of a series of selenylation products containing an adjacent aminoacyl group in a fast and efficient way, with high atom economy. The synthetic application of this method was demonstrated by taking advantage of the amide functionality as a nucleophile, directing group, and amide coupling partner. This work shows great potential in facilitating rapid construction of selenium‐containing DNA‐encoded chemical libraries (SeDELs), and lays the foundation for the development of selenium‐containing drugs.

Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation

“…However, this task is generally of big challenge due to the intractable contradiction that the highly functionalized DNA barcodes are water‐soluble and very sensitive, but their integrity must be maintained during the reaction process [63,64] . Despite this, the mild conditions, high yields and the suitability for nanomole‐scale parallel synthesis of this SeNEx click chemistry, as well as the successful experience of our group in the synthesis of DEL, [65–70] especially Se‐containing DNA‐encoded library ( Se DEL), [22,36,37,71] have prompted us to convert this newly developed reaction into on‐DNA synthesis.…”

Incorporating Selenium into Heterocycles and Natural Products─From Chemical Properties to Pharmacological Activities

“…Therefore, it is important to develop efficient and robust synthetic protocols to prepare either new or known Se-containing heterocyclic scaffolds with good functional group tolerance. (8) Considering that DNA-encoded library (DEL) technologies have emerged as a powerful strategy for rapid lead generation, 156 the development of DNA-compatible chemistry for the synthesis of a focused Se DNA-encoded library (SeDEL) 157 and modular or clickable synthetic methods to achieve the on-plate combinatorial synthesis of organoselenium screening libraries will be two powerful strategies to generate organoselenium hit compounds.…”

Bioinspired Selenium‐Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole‐Scale Medicinal Chemistry and Bioconjugation

“… [33,34] Both of them are similar to nature's biosynthesis of amide bonds (proteins) and phosphate diesters (DNA and RNA), driven by the nucleophilic exchange of the activated acid [1,35] . These mild and efficient SeNEx chemistry in biological systems are important clues for us to develop C−Se bond formation click chemistry [36–38] . Indeed, inspired by this, our group has recently designed benzoselenazolone (BSEA, core of Ebselen), [36,37] and benzothiaselenazole‐1‐oxide (BTSA) [38] as novel bifunctional Se sources for efficient C−Se bond formation by employing in situ formed C(sp 2 )‐Rh III species [36] and free indole, [37,38] as nucleophiles, respectively.…”